The present invention relates to a new thienopyridine derivative useful as an anti-inflammatory drug, especially as a drug for treating arthritis, or a salt thereof. The thienopyridine derivative or a salt thereof also has bone resorption inhibitory activity and is useful as a drug for preventing and treating osteoporosis. in addition, the thienopyridine derivative or a salt thereof is useful, for example, as a drug for preventing and treating immune-related diseases, such as an immunosuppressant.
Arthritis, an inflammatory disease of the joint, occurs in various forms such as rheumatoid arthritis and related diseases with joint inflammation.
Rheumatoid arthritis, also called chronic rheumatism, in particular, is a chronic multiple arthritis characterized by inflammatory changes in the synovial membrane of the articular capsule inner layer. Arthritic diseases like rheumatoid arthritis are progressive and cause joint disorders such as deformation and acampsia, often resulting in severe physical disorder due to a lack of effective treatment and subsequent deterioration.
Traditionally, these forms of arthritis have been chemotherapeutically treated with various drugs including steroids and other adrenocortical hormones (e.g., cortisone), non-steroidal anti-inflammatory drugs (e.g., aspirin, piroxicam, indomethacin), gold-containing drugs (e.g., auro-thiomalate), antirheumatic drugs (e.g., chloroquine preparations, D-penicillamine), anti-gout drugs (e.g., colchicine) and immunosuppressors (e.g., cyclophosphamide, azathioprine, methotrexate, levamisole).
However, these drugs have drawbacks such as severe adverse reactions, adverse reactions hampering the drug""s long-term use, a lack of efficacy and a failure to be effective against already-occurring arthritis.
Accordingly, there is a need for the development of a drug which exhibits excellent prophylactic/therapeutic action on arthritis with low toxicity in clinical situations.
Heretofore, various compounds have been synthesized as thieno[2,3-b]pyridine derivatives including those described in the Bulletin of the Chemical Society of Japan, Vol. 61, p. 4431 (1988), Chemical and Pharmaceutical Bulletin, Vol. 36, p. 4389 (1988), Phosphorus, Sulfur and Silicon, Vol. 73, p. 127 (1992), Chemical and Pharmaceutical Bulletin, Vol. 40, p. 1376 (1992) and Khim Geterotsikl Soedin, Vol. 1, p. 124 (1987). However, these compounds are limited to the structure in which the substituent at the 6-position in the thieno[2,3-b]pyridine skeleton is a methyl group. Also, no description of anti-inflammatory action, bone resorption inhibitory action or immunosuppressant action is given for these known thienopyridine derivatives.
One object of the present invention is to provide novel thienopyridine derivatives which have anti-inflammatory activity and useful, for example, as anti-inflammatory drugs, especially as drugs for treating arthritis, as well as which have bone resorption inhibitory activiy and immunosuppressant activity and useful as drugs for inhibiting bone resorption and immunosuppressants, or salts thereof.
Another object of the present invention is to provide a pharmaceutical composition useful for treating inflammation, in particular, arthritis, for preventing or treating arthritis, for inhibiting bone resorption and immunosuppressant which comprising the novel thienopyridine derivative or a salt thereof as an effective component.
These objects as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following description.
The present inventors found that a novel thienopyridine derivative represented by the following formula (A) has antiarthritic activity and serves well as a joint destruction suppressor and also found that the thienopyridine derivative has bone resorption inhibitory activity which functions on a bone directly and serves well as a bone resorption inhibitory drug. In addition, the present inventors found that the thienopyridine derivative represented by the formula (A) is useful, for example, as a drug for preventing or treating immune-related diseases. The present inventors further made investigations based on these findings and completed the present invention.
That is, according to the present invention, there is provided a compound represented by the formula (A): 
wherein W represents Cxe2x80x94G or Cxe2x80x94Gxe2x80x2 (G represents a carboxyl group which may be esterified; and Gxe2x80x2 represents a halogen atom); X represents an oxygen atom, a sulfur atom which may be oxidized or xe2x80x94(CH2)qxe2x80x94 (q represents an integer from 0 to 5); R represents an optionally substituted amino group or an optionally substituted heterocyclic group; the ring B represents an optionally substituted nitrogen-containing 5- to 7-membered ring; L represents a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group or an optionally substituted sulfonyl group, provided that, when W is Cxe2x80x94G, L is a hydrogen atom, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted thiocarbamoyl group or an optionally substituted sulfonyl group; n represents 0 or 1; and the ring A may have a substituent; or a salt thereof.
The present invention also provides a process for producing a compound of the formula (A) or a salt thereof and a pharmaceutical composition comprising as an effective component a compound of the formula (A) or a pharmaceutically acceptable salt thereof, in particular, a pharmaceutical composition for preventing or treating inflammation, a pharmaceutical composition for preventing or treating arthritis, a pharmaceutical composition for preventing or treating rheumatism, a pharmaceutical composition for preventing or treating chronic rheumatoid arthritis, a pharmaceutical composition having bone resorption inhibitory activity, a pharmaceutical composition for preventing or treating osteoporosis, a pharmaceutical composition having cytokine-production inhibitory activity, a pharmaceutical composition for preventing or treating autoimmune diseases, and a pharmaceutical composition for preventing rejection after organ transplantation.